Oncogenic PIK3CA reprograms glutamine metabolism to drive bladder cancer progression
11 affiliations
- 1Department of Molecular and Cellular Biology, Baylor College of Medicine
- 2Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine
- 3Department of Molecular and Human Genetics, Baylor College of Medicine
- 4Advanced Technology Cores, Baylor College of Medicine
- 5Georgia Cancer Center, Augusta University
- 6Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center
- 7Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine
- 8Scott Department of Urology, Baylor College of Medicine
- 9Department of Urology, Medical College of Georgia
- 10Department of Medicine, Harvard Medical School, Veterans Affairs Boston Healthcare System
- 11Department of Urology, University of Texas Southwestern Medical Center
Abstract
Background Genomic analysis has revealed that approximately 40% of bladder cancer (BLCA) tumors harbor alterations in the PI3K/AKT pathway, with PIK3CA mutations occurring in 15–25% of cases. PIK3CA, which encodes the catalytic p110α subunit of PI3K, plays a critical role in regulating cell survival, proliferation, and metabolism. However, the metabolic and functional consequences of PIK3CA mutations in BLCA remain poorly defined. Methods To investigate the role of PIK3CA mutations in BLCA, we performed targeted sequencing on tumors from patients, identifying recurrent alterations. Using CRISPR/Cas9 knock-in models in SCaBER and UM-UC-3 cell lines, we introduced the PIK3CA E545K mutation to study its effects. We conducted transcriptomic profiling, targeted metabolomics, and stable isotope tracing to assess metabolic reprogramming. Functional assays measured proliferation, mitochondrial complex I activity, and glutaminolysis. Orthotopic xenografts in mice were used to evaluate in vivo tumor growth and metabolism. Results PIK3CA mutations were present in 20% of cases, consistent with TCGA data. The E545K and E545Q hotspots accounted for 70% of these mutations. PIK3CA E545K strongly activated PI3K/AKT signaling. Transcriptomic analysis revealed enrichment of OXPHOS, fatty acid metabolism, and mTORC1 signaling. Metabolomics indicated changes in TCA cycle metabolites and enhanced reductive carboxylation of glutamine to citrate, driving fatty acid synthesis. Mutant cells showed increased expression of GLS1 and FASN, higher proliferation rates, and elevated mitochondrial complex I activity. In vivo, PIK3CA-mutant xenografts displayed significantly increased tumor growth. Conclusion PIK3CA mutations are frequent drivers of metabolic reprogramming in BLCA, leading to increased glutamine flux, elevated OXPHOS activity, and enhanced fatty acid synthesis, all of which contribute to tumor progression. These findings provide the first comprehensive evidence that PIK3CA-driven metabolic alterations are both biomarkers of aggressive disease and actionable therapeutic targets. The efficacy of PI3Kα inhibition in combination with metabolic targets may support its potential in precision medicine for PIK3CA-mutant BLCA and highlights the value of integrating metabolic biomarkers into treatment strategies for advanced BLCA.
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BibTeX
@article{reddy2026oncogenic,
title = {{Oncogenic PIK3CA reprograms glutamine metabolism to drive bladder cancer progression}},
author = {Karthik Reddy Kami Reddy and Vasanta Putluri and Danthasinghe Waduge Badrajee Piyarathna and Jun Hyoung Park and Aaditya Krishna Arun and Sachin B Jorvekar and Yongchao Dou and Mohammed Khurshidul Hassan and Chandra Sekhar Amara and Abu Hena Mostafa Kamal and Chandra Shekar R. Ambati and Jun Xu and Daniel Kraushaar and Adriana Langer Gramer and Allison C Bellman and Leomar Y Ballester and Yuan Xu and Robert Taylor Ripley and Seth P Lerner and Roni J Bollag and Martha K Terris and Chong-Xian Pan and Benny Abraham Kaipparettu and Yair Lotan and Nagireddy Putluri},
journal = {Cell Communication and Signaling},
year = {2026},
month = jul,
doi = {10.1186/s12964-026-03058-w},
url = {https://doi.org/10.1186/s12964-026-03058-w},
note = {CC BY},
}
RIS
TY - JOUR
TI - Oncogenic PIK3CA reprograms glutamine metabolism to drive bladder cancer progression
AU - Karthik Reddy Kami Reddy
AU - Vasanta Putluri
AU - Danthasinghe Waduge Badrajee Piyarathna
AU - Jun Hyoung Park
AU - Aaditya Krishna Arun
AU - Sachin B Jorvekar
AU - Yongchao Dou
AU - Mohammed Khurshidul Hassan
AU - Chandra Sekhar Amara
AU - Abu Hena Mostafa Kamal
AU - Chandra Shekar R. Ambati
AU - Jun Xu
AU - Daniel Kraushaar
AU - Adriana Langer Gramer
AU - Allison C Bellman
AU - Leomar Y Ballester
AU - Yuan Xu
AU - Robert Taylor Ripley
AU - Seth P Lerner
AU - Roni J Bollag
AU - Martha K Terris
AU - Chong-Xian Pan
AU - Benny Abraham Kaipparettu
AU - Yair Lotan
AU - Nagireddy Putluri
PY - 2026
DA - 2026/07/01
JO - Cell Communication and Signaling
DO - 10.1186/s12964-026-03058-w
UR - https://doi.org/10.1186/s12964-026-03058-w
AB - Background Genomic analysis has revealed that approximately 40% of bladder cancer (BLCA) tumors harbor alterations in the PI3K/AKT pathway, with PIK3CA mutations occurring in 15–25% of cases. PIK3CA, which encodes the catalytic p110α subunit of PI3K, plays a critical role in regulating cell survival, proliferation, and metabolism. However, the metabolic and functional consequences of PIK3CA mutations in BLCA remain poorly defined. Methods To investigate the role of PIK3CA mutations in BLCA, we performed targeted sequencing on tumors from patients, identifying recurrent alterations. Using CRISPR/Cas9 knock-in models in SCaBER and UM-UC-3 cell lines, we introduced the PIK3CA E545K mutation to study its effects. We conducted transcriptomic profiling, targeted metabolomics, and stable isotope tracing to assess metabolic reprogramming. Functional assays measured proliferation, mitochondrial complex I activity, and glutaminolysis. Orthotopic xenografts in mice were used to evaluate in vivo tumor growth and metabolism. Results PIK3CA mutations were present in 20% of cases, consistent with TCGA data. The E545K and E545Q hotspots accounted for 70% of these mutations. PIK3CA E545K strongly activated PI3K/AKT signaling. Transcriptomic analysis revealed enrichment of OXPHOS, fatty acid metabolism, and mTORC1 signaling. Metabolomics indicated changes in TCA cycle metabolites and enhanced reductive carboxylation of glutamine to citrate, driving fatty acid synthesis. Mutant cells showed increased expression of GLS1 and FASN, higher proliferation rates, and elevated mitochondrial complex I activity. In vivo, PIK3CA-mutant xenografts displayed significantly increased tumor growth. Conclusion PIK3CA mutations are frequent drivers of metabolic reprogramming in BLCA, leading to increased glutamine flux, elevated OXPHOS activity, and enhanced fatty acid synthesis, all of which contribute to tumor progression. These findings provide the first comprehensive evidence that PIK3CA-driven metabolic alterations are both biomarkers of aggressive disease and actionable therapeutic targets. The efficacy of PI3Kα inhibition in combination with metabolic targets may support its potential in precision medicine for PIK3CA-mutant BLCA and highlights the value of integrating metabolic biomarkers into treatment strategies for advanced BLCA.
SN - 1478-811X
ER -